LIS1 MONOALLELIC DELETION DRIVES SUBTLE DENTATE GYRUS DEVELOPMENTAL ABNORMALITIES AND PERSISTENT ALTERATIONS IN ADULT NETWORK ACTIVITY

LIS1 mutations are a well-established cause of type I lissencephaly, a severe neurodevelopmental disorder characterized by defective cortical folding, disrupted lamination, epilepsy, and cognitive impairment. These phenotypes are linked to the role of LIS1 as a key regulator of the dynein motor complex, essential for neuronal migration, cell division, and axonal transport. However, the impact of LIS1 dysfunction on postnatal hippocampal development remains incompletely understood. Here, we investigated hippocampal alterations in the Lis1/sLis1 mouse model, focusing on dentate gyrus (DG) development and function. At postnatal day 4 (P4), immunohistochemical analysis of GFAP revealed morphological abnormalities and a reduction in radial glial (RG) cells in the hippocampal secondary matrix. Nestin labeling further confirmed alterations in RG and neural precursor populations. To assess the functional consequences on neuronal migration, we electroporated GFP-expressing plasmids into the subventricular zone of P0 mice and analyzed neuronal positioning at P4. Mutant mice exhibited delayed migration of granule cell progenitors, a finding corroborated by Tbr2 immunostaining. Despite these early developmental defects, cresyl violet staining and NeuN immunohistochemistry indicated that overall DG layer thickness and organization were preserved in adulthood. To evaluate functional outcomes, we performed in vivo local field potential recordings, revealing a significant increase in theta-band power in mutant mice, consistent with altered DG network activity. Additionally, coherence analyses demonstrated enhanced interhemispheric DG connectivity and increased DG–DG coupling. Together, our findings indicate that LIS1 dysfunction disrupts early DG development, particularly radial glia integrity and neuronal migration, leading to long-lasting alterations in hippocampal network dynamics.